The overall objective of this program is to define immune responses to SIV in Rhesus macaques which correlate with protective immunity with particular emphasis being placed on a comparison of antibody responses induced by vaccines derived from monocyte-tropic and T lymphocyte-tropic viruses. This subproject will probe humoral responses at the monoclonal antibody level in order to precisely identify epitopes or groups of epitopes which elicit potent neutralizing antibody responses in vivo in Rhesus macaques infected with experimental live SIV vaccines as well as in macaques manifesting long term survival of infection with pathogenic SIV strains. We will produce and characterize a large panel of rhesus monkey monoclonal antibodies (RhMAb) which reflect in vivo B cell recognition of SIV envelope glycoprotein epitopes. Each RhMAb will be characterized with respect to strain reactivity, binding to linear vs conformational epitopes, mapping of binding sites, and neutralizing activity. Since SIVmac, SIVmn and HIV-2 strains belong to the same group of lentiviruses and are serologically cross-reactive, it is likely that neutralizing epitopes in these viruses will be to some extent similar; however, it is far from certain whether there are important differences in the repertoire or function of neutralizing antibodies in each host species. This laboratory is involved in a parallel project to produce human MAbs to HIV-2 and thus we will have a unique opportunity to compare monoclonal antibody responses in both humans and macaques during chronic infections with a highly similar group of lentiviruses. We will also generate RhMAbs reactive with HIV-1 glycoproteins from macaques infected with chimeric SIV/HIV-1 (SHIV) vaccine constructs.